Abstract P1-18-35: MT-5111, a novel HER2 targeting engineered toxin body, under clinical development to overcome mechanisms of resistance to existing HER2 targeted therapies

Autor: Eric T Williams, Roger J. Waltzman, Jack P. Higgins, Asis K. Sarkar, Aimee Iberg, Erin Willert
Rok vydání: 2020
Předmět:
Zdroj: Cancer Research. 80:P1-18
ISSN: 1538-7445
0008-5472
DOI: 10.1158/1538-7445.sabcs19-p1-18-35
Popis: Engineered toxin bodies (ETBs) are differentiated, targeted therapeutics comprised of a proprietarily engineered form of Shiga-like Toxin A subunit (SLTA) genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action and are capable of forcing internalization, self-routing through intracellular compartments to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation of ribosomes. MT-5111 is a de-immunized ETB targeting HER2 for solid tumors. MT-5111 works through a novel mechanism of direct cell-kill, via enzymatic ribosome inactivation, and may not be subject to resistance mechanisms that exist for TKI, ADC, or antibody modalities. MT-5111 is a 55 kilodalton protein and may have improved tumor penetration features in the solid tumor settings. MT-5111 has been designed to bind a HER2 domain distinct from the trastuzumab and pertuzumab binding sites and retains binding to HER2 and cell-kill activity even in the presence of these monoclonal antibodies. As such, MT-5111 may have the potential to be combined with other HER2 targeted therapies. MT-5111 specifically binds and kills HER2 expressing cells in a manner consistent with SLTA-mediated cellular cytotoxicity. MT-5111 effectively killed eight of nine cell lines with moderate to high HER2 surface expression, five of which were breast cancer cell lines. No cytotoxicity was observed on multiple HER2-negative cell lines at MT-5111 levels >500 fold higher than IC50 levels in HER2-positive cells. The cytotoxic activity of MT-5111 (picomolar range) is dependent on the presence of the HER2 receptor, and efficient killing is observed prior to receptor saturation. As a large molecule protein, MT-5111 is not a substrate of drug efflux transporters such as MDR1 which has been demonstrated to be one of the primary mechanisms of resistance to the antibody drug conjugate T-DM1. Specifically, T-DM1 resistant cell lines with moderate HER2 expression (JIMT-1 breast cancer and SNU-216 gastric cancer lines) were sensitive to MT-5111 but were not effectively killed by T-DM1, highlighting the benefit of a novel MOA to treat resistant disease. Further, MT-5111 has demonstrated effective cell-killing in vitro against trastuzumab resistant cell lines (HCC1954 breast cancer). MT-5111 binds both human and cynomolgus monkey HER2 protein similarly. From repeat dose studies in non-human primates, the serum exposure of MT-5111 was used to model the pharmacokinetics of MT-5111 dosing in human. This modelling suggests that MT-5111 can be administered at doses in humans above the IC50 required for HER2-specific cellular cytotoxicity in vitro. MT-5111 was designed to achieve a short half-life to allow for efficient tumor cell targeting but minimal serum exposure time to avoid systemic effects over time. This short half-life was confirmed in primates (t1/2 of ~2 to 5 hours). A Phase 1, first in human, open-label dose escalation, and expansion study of MT-5111 (NCT04029922) in subjects with HER2-positive solid tumors whose disease has progressed after treatment with other approved therapies is open for enrollment. In conclusion, MT-5111 represents a novel HER2 targeted therapy which could provide benefit in subjects with HER2-positive cancers and potentially overcome mechanisms of tumor resistance to existing HER2 targeted therapies. Citation Format: Jack P Higgins, Asis Sarkar, Eric T Williams, Aimee Iberg, Roger Waltzman, Erin K Willert. MT-5111, a novel HER2 targeting engineered toxin body, under clinical development to overcome mechanisms of resistance to existing HER2 targeted therapies [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-35.
Databáze: OpenAIRE
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